How does teriparatide work in a postmenopausal woman with severe osteoporosis refractory to anti‑resorptive therapy?

Mechanism of Action of Teriparatide in Severe Osteoporosis

Teriparatide (recombinant human parathyroid hormone 1-34) works by stimulating new bone formation through preferential activation of osteoblastic activity over osteoclastic activity, creating a net anabolic effect that increases bone mass, improves bone microarchitecture, and enhances bone strength. 1, 2, 3

Primary Mechanism: Anabolic Bone Formation

Teriparatide is the first and only FDA-approved anabolic agent for osteoporosis, fundamentally different from antiresorptive therapies. 1 The drug works through a sequential process:

• Initial phase: Teriparatide transiently increases bone resorption, followed by a more pronounced and sustained increase in bone formation, resulting in net bone gain 1
• Cellular action: The drug preferentially stimulates osteoblasts (bone-building cells) over osteoclasts (bone-resorbing cells), creating positive bone balance 4, 3
• Bone surface effects: New bone formation occurs on both trabecular (spongy bone) and cortical (compact bone) surfaces, including periosteal and endosteal surfaces 2, 5

Structural and Quality Improvements

Teriparatide improves multiple parameters of bone quality beyond simple density increases 2:

• Bone mineral density (BMD): Increases BMD at spine and hip, with lumbar spine showing 5.9-9.0% increases 3
• Bone microarchitecture: Enhances trabecular connectivity and cortical bone structure 2, 6
• Bone size: Increases periosteal circumference and cross-sectional area, particularly at cortical sites like the radius 5
• Mechanical strength: Improves moments of inertia and structural parameters that predict fracture resistance 5

Clinical Efficacy in Severe Osteoporosis

For postmenopausal women with severe osteoporosis refractory to antiresorptive therapy, teriparatide demonstrates superior fracture reduction compared to continued antiresorptive treatment. 1, 6

• Vertebral fractures: Reduces risk by approximately 65-70% compared to placebo 6, 4
• Non-vertebral fractures: Reduces risk by approximately 45-53% 6, 4
• Radiographic vertebral fractures: Shows 66 fewer events per 1000 patients compared to bisphosphonates at 24 months 1

Critical Treatment Considerations

A major caveat is that teriparatide's anabolic effects decline with time, and discontinuation results in rapid bone loss unless followed by antiresorptive therapy. 2, 6

• Treatment duration: Maximum 2 years (24 months) during a patient's lifetime 1, 7
• Sequential therapy required: Must be followed by bisphosphonate or denosumab to maintain BMD gains 1, 2, 6
• Prior antiresorptive use: If bone turnover is markedly suppressed from previous bisphosphonate therapy, teriparatide's effects on BMD may be transiently delayed 2

Paradoxical PTH Effect

An important biological paradox: daily intermittent PTH administration is anabolic to bone, while continuous elevated PTH (as in hyperparathyroidism) is catabolic and causes bone loss. 6 The intermittent exposure pattern is critical to the anabolic effect, though the complete mechanism remains incompletely understood 6.

Positioning for Refractory Cases

Teriparatide is specifically indicated for very high-risk patients who have failed antiresorptive therapy, defined as: 1, 7

• Fractures occurring despite adequate bisphosphonate treatment 7
• T-score ≤ -3.5 with multiple prevalent fractures 7
• Recent fracture (within past 12 months) in context of severe osteoporosis 1
• Multiple clinical osteoporotic fractures or multiple risk factors for fracture 1

The American College of Physicians recommends teriparatide followed by a bisphosphonate specifically for females with very high fracture risk, representing conditional (not strong) recommendation based on moderate-to-low certainty evidence. 1

Contraindications in Cancer Patients

Critical warning: Teriparatide is contraindicated in patients with bone metastases or history of malignancy prone to bone metastasis. 1, 7 The marked increase in bone turnover may theoretically promote propagation of microscopic bone metastases through liberation of bone-derived growth factors and cytokines 1. Additional contraindications include open epiphyses, Paget's disease, and prior skeletal radiation 1, 7.